AR-NTD antagonist K53 is a potent, selective antagonist of androgen receptor N-terminal domain (AR-NTD) with SPR KD of 25.1 uM (AR-NTD-AF1 fragment), exhibits potent anti-proliferative activity in enzalutamide-resistant prostate cancer cells.
K53 not only outperforms the second-generation AR antagonist Enz in LNCaP cells but also effectively inhibits the proliferation of enzalutamide-resistant 22Rv1 and LNCaP-EnzR cells.
K53 does not act through the canonical ligand-binding pocket.
K53 dose-dependently inhibits dihydrotestosterone (DHT)-induced AR activity with IC50 of 2.33 uM in LNCaP-ARR2PB-eGFP cell line.
K53 does not antagonize the activity of progesterone receptor (PR), glucocorticoid receptor (GR), or mineralocorticoid receptor (MR) induced by exogenous hormones, respectively, nor does it activate PR or MR in the absence of hormones.
K53 significantly downregulates the mRNA expression of canonical AR target genes including KLK3 (PSA), FKBP5, and TMPRSS2 in a concentration-dependent manner in LNCaP cells.
K53 effectively disrupts AR signaling at both the transcriptional and translational levels.